Catechol estrogens (CE's) are a major group of active natural estrogen metabolites, which are synthesized in various organs (liver, brain and pituitary) from estrone and estradiol and are found in human plasma (50-100 pg/ml) and urine. These compounds exhibit a spectrum of activities which is unique amongst estrogen metabolites so far identified, in that they are capable not only of interacting with tissue estrogen receptors, but also of entering directly into pathways of biogenic amine metabolism. The biological significance of CE's remains ill-defined. We propose to further investigate the formation tissue distribution and mode of action of CE's using the following experimental approaches: (1) The uptake, retention and subcellular distribution of (3H) CE's by estrogen target tissues will be studied, in rats. Quantitative aspects of the formation of CE's by neuroendocrine tissues will be further investigated using isolated perfused rat and rhesus monkey brains. (2) Levels of bound and free CE's will be measured in rat and human plasma. The effects of variations in physiologic state on plasma CE concentrations will be determined. (3) An attempt will be made to differentiate between estrogen receptor mediated and catecholamine-related effects of CE's, using 17 alpha CE isomers. Biochemical properties of these isomers will be further investigated and correlated with their pharmacologic effects. These studies will hopefully increase our understanding of the physiologic role and mechanism of action of this important group of estrogen metabolites.